Aerosol composition containing butoxymonoether of a polyoxyalkylene glycol



United States Patent 3,456,052 AEROSOL COMPOSITION CONTAINING BU-TOXYMONOETHER OF A POLYOXYAL- KYLENE GLYCOL Marvin Gordon, Baltimore,Md., assignor to Garrett Laboratories, Inc., a corporation of MarylandNo Drawing. Filed Sept. 28, 1965, Ser. No. 491,030 Int. Cl. A61k 9/06,21/00 U.S. Cl. 42445 7 Claims ABSTRACT OF THE DISCLOSURE An improvedpharmaceutical aerosol ointment base system which consists essentiallyof a propellant, an ointment base and an efiective amount of amedicament. The ointment base consists essentially of a butoxymonoetherof a polyoxyalkylene glycol which is substantially completely soluble inthe propellant.

This invention relates to improvements in self-propelling medicinalcompositions and methods of their use and relates more particularly toan improved pharmaceutical aerosol ointment base system.

There have been various self-propelling therapeutic preparationssuggested heretofore which provide for the topical application of aselected pharmaceutically active material to an injured or infected areaof the human body. Many of the prior art materials merely dispense themedicament in the form of a spray form a dispersion or solution of thesame in a propellant maintained under pressure in an aerosol container.Such systems suffer numerous disadvantages, perhaps the most significantof which is their inability to maintain the active ingredient in contactwith a limited area of the body for a time sufficient to allow the sameto provide its healing properties. Generally, the spray resulting fromsuch a composition has an extremely low viscosity, frequently on theorder of water, whereby the material has a tendency to run from the areaonto which it is dispensed causing great inconvenience to the patient aswell as a substantial loss of medicament. Moreover, these materials aregenerally cold in use because of the rapid evaporation of the propellantwhich forms the major constituent of the composition. In view of thefact that the area being treated is normally quite sensitive, such acharacteristic is extremely undesirable.

An additional difficulty frequently encountered with spray materials ofthis type is their inability to provide, especially in a reproduciblemanner, a uniform application of the medically active ingredientthroughout the use of the entire aerosol container. This is particularlydue to the fact that the active material is frequently merely dispersedin the propellant whereby it will have a tendency to settle to thebottom. Further, the dispersed material will sometimes clog the spraydispensing valve whereby the pattern of the atomized particles will varywith the use of the container, substantially decreasing the likelihoodthat a consistent quantity of medicament can be dispensed in aparticular time.

It has been proposed to overcome certain of the above disadvantages bytopically applying the medicament in the form of an ointment spray.However, the attempt to self-propellant ointment base causes manydifficulties of its own. Although the ointment systems suggested to datemay improve the healing capabilities of a self-propelling medicinalcomposition by providing a non-runny film for maintaining the activeingredient in contact with the afiected bmly area, there are manyproblems with which these prior art materials have not been able to dealeffectively.

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In the first place, While the ointment base systems currently in use doprovide a means for applying a film of a somewhat stable material to thebodily area being treated whereby prolonged contact with a medicamentmay be realized, it has been found that they do not permit suflicientlyrapid release of the active component of the composition to effect theproper healing characteristics. Moreover, the nature of such prior artsystems is such that, for the most part, they are water insoluble andproduce a greasy film on the skin surface. Thus, in addition to theobvious cosmetic problems resulting from the use of such materials, theyare difficult to remove whereby it sometimes becomes necessary tocontact a sensitive body area with an irritating solvent or to applyundesirable pressure to the area to cleanse the same. Further, the oilynature of the ointment base in some such systems has a tendency to soilclothing with which it comes in contact. Also, dust and dirt from theenvironment have a great tendency to stick to these ointment bases andthe difiiculty in removing the same will frequently result in thepresence of a contaminating film in contact with the body area beingtreated whereby the therapeutic value of the composition may bedefeated.

Further, the difiiculty in substantially uniform applications referredto hereinabove is even more prevalent in materials of this type sincethe ointment base and certain of the additional materials includedtherewith are generally merely dispersed in the propellant whereby aneven greater tendency to clog the spray dispensing head results.

In an attempt to improve the properties of the applied materials whilelimiting the area to be covered to a desired degree, it has beensuggested that self-propelling compositons in the nature of a foam incontrast to an atomized spray be utilized. However, in order to providea foam which will be quick-breaking so that proper use of the same isfeasible, it is necessary to include a substantial quantity ofextraneous materials such as surface active agents and the like therebyincreasing the expense of manufacture as well as toxicity problemsencountered with a medicinal composition. Moreover, a foam cannotprovide the distribution and substantially uniform film which isrealized with a properly atomized spray. Further, in pharmaceuticalapplications, such foams suffer from relatively poor medicament releasewhereby their healing properties are substantially diminished.

Another significant disadvantage of foams, when considered in contrastwith sprays, particularly for medicinal compositions, is their inabilityto penetrate into the various crevices which are usually present in aninjured or infected area of the human body. Although a spray is capableof providing suflicient dispensing power to uniformly cover the entireaffected area, it is still an ideal method of application from thestandpoint of gentleness and comfort to the patient.

Generally, sprayable ointment compositions utilized in the past have hadas the major component of their ointment base, an oil, such as mineraloil, either by itself or in combination with other oils and thixotropicagents. Additionally, mineral oil bases including fibrous or other formsof various resinous materials such as polyethylene or the like, havebeen utilized in an attempt to improve some of the characteristics ofthe ointment base. However, all of these compositions have suifered fromthe various disadvantages mentioned hereinabove since they are generallyin the form of dispersions of a non-water soluble, greasy materialhaving relatively poor medicament release capabilities in use.Particular obstacles to overcome with such compositions is the provisionof substantially uniform and reproducible application as well asrelative ease in removal from a sensitive body area.

Similarly, attempts to use such materials as Carbowax,

a trademark for a particular series of polyethylene glycols produced byUnion Carbide Chemicals Company, while providing water solubility to theultimate ointment base, still results in a greasy film and raisescertain toxicity problems With respect to the aerosol application of thesame. Moreover, this material is generally insoluble in many of thepropellants which are most desirable for topical application tosensitive body areas, requiring either the use of a dispersion whichresults in non-uniform application, or the use of a propellant havingvarious undesirable characteristics such as irritation to the skin andpossible flammability.

Thus, it will be seen that although many attempts have been made toprovide an ideal self-propelling composition for topical application ofa pharmaceutically active material, each of the materials suggested todate has failed in one or more respects. It is to be understood that thedisadvantages of prior art materials discussed hereinabove are merelyillustrative and are not meant to be fully comprehensive in allrespects. However, it is apparent from the above background that theproduction of an optimum ointment base system and method of itsapplication has provided the industry with an intricate problem which ithas been unable to satisfactorily solve even after extensive research.

It is therefore a primary object of the instant invention to provide anointment base system and method of using the same which is free from theforegoing and other disadvantages. In this regard, it is a particularobjective of the instant inventive concept to provide an aerosolointment base which is relatively simple and inexpensive to manufactureand which results in the topical application of a pharmaceuticallyactive material in an easily controlled, substantially uniform, watersoluble, film from which the medicament is rapidly and continuouslyreleased to the area being treated.

Consistent with the above, it is a basic object of this invention toprovide a self-propelling medicinal spray wherein the ointment base, andpreferably the medicament or medicaments, are substantially fullysoluble in the propellant in order that the application of a desiredquantity of the active ingredients in a reproducible manner can beproduced from a conventional pressurized aerosol container, even afterextended use. Further along these lines, it is an important object ofthis invention, at least in its preferred form that there be completeand mutual solubility of the ingredients in order to preclude settlingof any of the components of the system and clogging of the spraydispensing head.

A further object of this invention is the provision of an aerosolointment base system which is uniquely compatible with substantially allcommonly utilized therapeutic materials and which is capable ofreleasing the same from the ointment film to the body area undertreatment in a rapid and continuous manner whereby effective healing ofthe injury or infection will be realized.

Yet another important objective of this invention is the provision of aself-propelling medicinal composition which is capable of penetratingthe area being treated while providing for gentle application. In asimilar vein, it is a special feature of at least the preferredcompositions of this invention that the applied spray be uniquely warmand non-irritating to a sensitive body area on which it is used, whileproducing a uniform film sufliciently viscous at body temperatures toremain in place and yet water soluble so that it can be easily removedWithout undesirable discomfort to the patient Other and further objectsof this invention reside in the particular materials utilized, thequantitative relationship between the same and the method of applyingthe composition to a body area requiring treatment. Still other objectswill in part be obvious and in part be pointed out as the description ofthe invention proceeds.

Consistent with the above background and objects of this invention, ithas been found that all of the desirable characteristics for aself-propelling therapeutic material set forth in detail therein, can beprovided by a sprayable ointment composition including apropellant-ointment base mixture and an effective quantity of one ormore medicaments, wherein the ointment base consists essentially of abutoxymonoether of a polyoxyalkylene' glycol substantially completelysoluble in the propellant in the quantities utilized. Thebutoxymonoether of a polyoxyalkylene glycol utilized in accordance withthe instant inventive concept is preferably prepared by reacting anapproximately 50/50 mixture by weight of ethylene oxide and1,2-propylene oxide with butyl alcohol according to the detailedexplanation of the production of such materials set forth, for example,in Roberts et a1. Patent No. 2,425,755 dated Aug. 18, 1947. It ispointed out in this patent that such materials are believed to becomplex mixtures of glycols of various molecular weights depending onthe length of the polyoxyalkylene chain, (OC H which is built up by theaddition of the oxyethylene group, OC H and the oxy 1,2-propylene group,OC H -CH to the individual molecules according to the following generalequation:

where y and z represent the mols of ethylene oxide and 1,2-propyleneoxide respectively; n is both 2 and 3 in a single molecule, the totalnumber of times n has a value of 2 being equal to y and the total numberof times It has a value of 3 being equal to z; and x is the total numberof such oxyalkylene groups, being equal to y+z. As can be seen, in thepreferred starting material which i an approximately 50/50 mixture byweight of ethylene oxide and 1,2-pr0pylene oxide, z is approximatelyequal to y.

The preferred materials are available commercially from the UnionCarbide Chemicals Company under the SO-HB series of their UCONlubricants. Basically, those materials identified as SO-HB-400,50-HB-660, 50HB2000, 50-HB-3520 and SO-HB-SIOO and mixtures of the samehave all been found to be useful although the 50-HB-5100 materialprovides particularly satisfactory results. These individual materialsdiffer in certain characteristic properties, and may be generallydesignated by their viscosity in S.U.S. (Saybolt Universal Seconds) atF. which ranges from 400 to 5100 depending on their molecular Weight,this value forming the sufiix in their identification in the UCON 50-HBseries.

For most purposes, it is preferred to limit the composition to its threebasic ingredients, that is, the propellant, the ointment base and themedicaments. In this regard, it has been found that the addition ofextraneous materials in any significant quantity substantially decreasesthe roperties of the ideal system resulting from the preferredcomposition.

It is particularly important to avoid the inclusion of any ingredientssuch as surface active, emulsifying, or foaming, agents in quantitieswhich tend to make it difficult to produce an atomized spray. Anymaterial proportion of such additives will result in the production of afoam in contrast to the discrete particles of a spray.

Similarly, the inclusion of extraneous materials in any substantialamount which are insoluble in the system is to be particularly avoidedin order to insure the uniformity of the composition and its applicationover an etxended period of time from a conventional aerosol container.

While it is to be understood that the self-propelling medicinal spray ofthe instant invention will preferably consist essentially of thepropellant-ointment base mixture and suitable medicaments, the additionof extremely small or insignificant quantities of other constituentswhich will not affect the basic desired characteristics of the system asspecified in detail throughout this application, is acceptable, althoughnot optimum. For example, in the use of a metallic aerosol container, itis sometimes desirable to include a small quantity of a non-toxiccorrosion inhibitor. Similarly, small percentages of cosmetic orpharmaceutically active ingredients which are not fully soluble in thesystem may be included so long as the percentage of the same isinsuflicient to overcome to any substantial degree the basic advantagesof the completely soluble, three component, composition which ispreferred. It is to be emphasized that the addition of such materials,while possibly acceptable in small quantities, is not preferred andtherefore should be avoided except for the provision of certain specialcharacteristics to the composition. It will be within the ordinary skillof this art to determine when such extraneous materials may be includedwithout significantly reducing the effectiveness of the basic system.

The quantitative ratio between the primary ingredients of thecomposition of this invention can vary within relatively large ranges.Preferably, the propellant constitutes the major component in thecomposition in order that satisfactory atomization and spraycharacteristics may be provided. In its broadest aspects, a suitableself-propelling material may include from as little as about 0.5 to asmuch as about 90 percent by weight of the butoxymonoether of apolyoxyalkylene glycol in the propellant-ointment base mixture, with thepropellant constituting sub stantially the remainder of the same.However, it will be obvious that the use of the minimum quantity ofointment base will result in a relatively cool, non-viscous system whichwould require a substantial quantity of spray to build up a thin layerof ointment. On the other hand, although a spray pattern can be producedwith only percent propellant, such a composition would be extremelyviscous and would provide a relatively thick ointment film which wouldnot be as easy to control. However, by varying the quantitative ratio ofpropellant to ointment base within the extreme limits of about 0.5 toabout 90 weight percent ointment base as indicated above, a systemhaving selective and satisfactory characteristics for a particularapplication can be provided. In this regard, it has been found that apreferred ratio from all respects includes from about 10 to about 25weight percent ointment base in the mixture.

With regard to the quantity of medicament utilized, this will of coursevary depending upon the particular medically accepted range of theparticular pharmaceutically active ingredient. In any event, effectivequantities of common therapeutic constituents are relatively low,generally in the vicinity of 1 or 2 percent based on the weight of theointment base in the composition.

It is to be understood that the type of medicament utilized may varysubstantially since, in general, and particularly in view of therelatively small percentages of the same in the overall composition, thecharacteristics of the aerosol ointment system is not dependent thereon.Further, various combinations of pharmaceutically active ingredients maybe utilized. For example, a common antiseptic or bactericidal materialsuch as Merthiolate or thimerosa may be utilized as the only medicament,or may be utilized in combination with an antibiotic such as bacitracin.Similarly, an anesthetic such as benzocaine or lidocaine may be usedalone or in combination with other pharmaceutically active materialssuch as hydrocortisone or the like. Similarly, combinations ofantibiotics such as bacitracin and neomycin sulfate may be used witheach other or with one or more of the steroids such as hydrocortisone orthe like.

Although, as has been pointed out in the immediately precedingparagraph, the aerosol ointment system of this invention is useful as acarrier for most any pharmaceutically active material, it has been foundthat it provides a unique base material for bacitracin andbacitracin-including medicaments and such a combination is therefore apreferred compoistion for use with the instant inventive concept.

There are various suitable non-toxic propellants which are well known inthe aerosol art. In general, these materials may be described as inert,liquefied, normally gaseous volatile materials in which thebutoxymonoether of a polyoxyalkylene glycol is substantially completelysoluble at the temperature normally encountered in use. Many of the wellknown fluorinated and chlorinated haloalkanes and mixtures of the samewith each other and with n butane and isobutane are completelysatisfactory in this regard. Suitable examples of individual and mixedpropellants are Du Ponts Freon-22 (CHCIF Allied Chemicals Genetron 142B(CHgCClFz) mixtures of Freon-22 and Freon-114 (CHClF -CClF CCIF Genetron142B and Freon-114 (CH CClF -CClF CClF Genetron 152A and Freon-114 (CHCHF CClF CClF Freon-l2 and Freon-11 (CCl F CCl F), and mixtures ofeither isobutane or butane with Genetron 142B, Genetron 152A, Freon-22or Freon-114. The preferred propellants from the standpoint ofsolubility, non-irritability and non-flammability are the mixtures ofFreon-12 or Freon-22 with Freon-114, but it will be understood that anyof the above materials and various other well known propellants andcombinations of propellants are suitable, the basic requirement beingthat the ointment base, and preferably all of the ingredients of thesystem, are soluble therein and that the propellant provide sufficientpressure to produce an atomized spray of the ointment base andmedicaments while completely evacuating a conventional aerosolcontainer.

The various compositions of the instant invention are convenientlyprepared according to any conventional aerosol packing procedure. Theindividual ingredients may be premixed before addition to the aerosolcontainers, or the various constituents may be separately introducedinto the containers by conventional cold fill or pressure methods. Inoperation, the composition is confined within the aerosol container atthe vapor pressure of the propellant and on opening the spray dispensingvalve, which may be of any conventional construction, the pressure isreleased to produce a fine ointment mist of the desired characteristics.A substantially uniform and reproducible layer of the ointment base andmedicaments may be readily applied to an injured or infected body areain this manner. The resultant film is air pervious in order to provide abreathing covering which permits access of air and oxygen to theaffected area thereby improving the healing characteristics. Further, anointment film produced in this manner is found to simultaneously permitextremely fast release of the pharmaceutically active ingredient to thebody area being treated.

In packing the pressurized aerosol containers, the metallic shell, thespray dispensing head and the constituents of the composition may bepresterilized or handled in any medically accepted manner. The aerosolcontainer may then be filled and maintained at a relatively cooltemperature while cold propellant is added following which the containermay be closed while maintained at the low temperature. Other fillingcycles may be used such as mixing the ointment and the propellant andcold filling, or the composition may be pressure-filled at highertemperatures. Various such methods of packing are conventional and thepresent compositions may be handled by any of the known procedures thusbeing readily adapted for use with any of the equipment currentlyavailable. Preferably, the materials are sufliciently intermixed priorto, or during the filling procedure that a substantially uniformsolution is produced thereby precluding any settling or valve cloggingproblems in subsequent use of the aerosol dispenser.

As mentioned hereinbefore a wide variety of active ingredients may beincluded in the compositions of the instant invention. In this regard,the term medicament as utilized throughout this specification and in theappended claims, is to be interpreted as one or more cosmetic ortherapeutically active ingredients which are suitable for topicalapplication in the form of a fine mist or spray. Such materials areparticularly useful in the treatment of open or ulcer-ous wounds orburns and various It will now be seen that there is herein provided animproved aerosol ointment base system and method of using the same whichsatisfies all of the objectives of the instant invention, and others,including many advantages of great practical utility and commercialimportance.

dermatological conditions where it is important to pro- What is claimedis: vide an uncontaminated coating containing therapeutic 1. An aerosolcomposition consisting essentially of an ingredients in a quick, gentlemanner with relative ease eifective quantity of a medicament selectedfrom the of removal for subsequent applications of additional groupconsisting of antiseptic, antibiotic, anesthetic and quantities of theactive ingredients or merely for cleans- 1O hydrocortisone medicamentsand mixtures thereof and a ing the affected area. mixture of apropellant and an ointment base, said oint- Although it is believed thatthe instant inventive conment base being present in from about 0.5 to 90percent cept can be readily understood from the preceding de by weightof said mixture of propellant and ointment scription, the followingtable sets forth various illustrabase with the remainder of said mixturebeing said propeltive examples, in which percents are by weight unless15 lant, said ointment base having a viscosity of from about otherwisenoted: 400 to 5100 S.U.S. at 100 F. and consisting essentially of aTABLE 1 Ointment Example Base, Number Percent Propellant, Percent ActiveIngredients 2 Comments Freon-22-114: 1a 0. 5 99.5 Satisfactory, but thinand cool. Particularly 1b excellent, spray and release characteris- 1c25 tics. 1d 90 Satisfactory, but relatively viscous and difiicult tocontrol. 2 Freon-22, 85 Neomycin Sulfate, 0.5 percent Good. 3 Freon-114,80 Bacitracin, t500 units; Neomycin Sulfate, Particularly goodantibiotic release. 0.5 percen Penicillin G Potassium: fig 30 1,000units 0 2,000 units.- 4c 20 5 000 units Satisfactory 4d 20 80 10,000units 5 10 "Genetron 152 Fr 4, 90 Tetracycline HG], 3 percen od. 6 15Freon-12414, 85 Polymyxin B Sulfate, 10,000 units; Baci- Particularlygood release.

tracin, 500 units. 7 Genetron 142B, 75 Poly-inyxin B Sulfate, 10,000units; Neo- Particularly good.

mycin Sulfate, 0.5 percent; Bacitracin, 500 units. 15 Fre0n-22-114, 85Bacitracin, 500 units; Neomycin Sulfate, Particularly good antibioticrelease plus 0.5 percent; Bcnzocaine, 2 percent. anesthetic action. 10Genetron 142B"Freon12, 90 Hydrocortisone, 1 percent; Neomycin Good.

Sulfate, 1.5 percent; Bacitracin, 500 units. 25 Freon-12-11, 75-.."Neomycin Sulfate, 5/10 percent; Triam- Do.

cinoloue Acetonide, 0.1 percent. n 11 15 Butane-Freon-114,85.--Hydrocortisone, 0.5 percent; NeomycmAntunflammation,antibioticandanesthetic Sulfate, 0.5 percent; Lidocaine,2.5 properties. percent. 12 10 Freon-22414, 90 Thirnerosal, 0.1 percentGood bacteriostat and fungistat.

1 Butoxymonoether of a polyoxyalkylene glycol. 2 U.S.P. units or percentper gram of ointment base.

Tests to date of the compositions of this invention from the standpointof medical acceptability and toxicity in various regards have all beensatisfactory. Such tests have included oral dose and inhalation studiesin rats as well as skin penetration and irritation and eye injurystudies in rabbits.

It is to be understood that although various specific propellants andquantitative ratios of the components of the aerosol ointment basesystem have been set forth in the above table, in each instance, thesecriteria may be varied within the broad ranges and classes of materialset forth herein without substantially aifecting the characteristicproperties of the ointment film resulting therefrom. However, it mightbe pointed out again that particularly advantageous results such asmedicament release and the like are generally found withbacitracin-containing compositions. Further, comparison of thecompositions of this invention with similar self-propelling ointmentsystems wherein the butoxymonoether of a polyoxyalkylene glycol isreplaced by other ointment bases such as those using mineral oil as amajor component, results in an ointment film which was unsatisfactoryfrom the standpoint of either cosmetic or therapeutic characteristics.Moreover, the compositions of the instant invention had up to percentbetter medicament release than those utilizing prior art ointment bases.Similarly, the compositions of this invention were more easily anduniformly applied and more readily removed without irritating theinfected or injured areas of the body being treated.

butoxymonoether of a polyoxyalkylene glycol prepared by reacting anapproximately 50/50 mixture by weight of ethylene oxide and1,2-propylene oxide with butyl alcohol, said propellant being selectedfrom the group consisting of fluorochloroalkanes having 14 carbon atoms,and mixtures of the same with each other and with butane and isobutane,said butoxymonoether of a polyoxyalkylene glycol being soluble in saidpropellant in the quantities utilized.

2. The composition defined in claim 1 wherein said butoxymonoether of apolyoxyalkylene glycol constitutes from approximately 10 to 25 percentby weight of said propellant-ointment base mixture and has a viscosityof approximately 5100 S.U.S. at F.

3. The composition defined in claim 1 wherein said butoxymonoether of apolyoxyalkylene glycol constitutes from approximately 10 to 25 percentby weight of said propellant-ointment base mixture.

4. The composition defined in claim 1 wherein said butoxymonoether of apolyoxyalkylene glycol has a viscosity of approximately 5100 S.U.S. 100F.

5. The composition defined in claim 1 wherein said medicament isselected from the group consisting of thimerosal, bacitracin,benzocaine, lidocaine, hydrocortisone, neomycin sulfate, penicillin,tetracycline, polymixin B sulfate, and mixtures thereof.

6. The compositions defined in claim 5 wherein said medicament isbacitracin and is present in an amount of from approximately 250-1000U.S.P. units per gram of ointment base.

7. The composition defined in claim 5 wherein said medicament includesbacitracin.

References Cited UNITED STATES PATENTS 5 Roberts et a1. 260-615 Heilig167-63 Siegal et a1 167-63 Noseworthy 167-63 Silson et a1. 167-82 10Hellbaum 167-63 Gross et a1. 167-63 XR 10 OTHER REFERENCES ShepherdAerosols: Science and Technology, 1961, pp.

ALBERT T. MEYERS, Primary Examiner D. R. MAHANAND, Assistant ExaminerUS. Cl. X.R.

